Diabetic nephropathy is the leading cause of end-stage renal disease in the United States. Microalbuminuria (albumin excretion rate between 30-300 mg/day) is the earliest clinically recognizable stage of the disease. Currently, no reliable clinical markers are available that allow us to identify diabetic patients at risk to develop nephropathy. The renin angiotensin system (RAS) is implicated in its pathogenesis. Skin manifestations of diabetic microangiopathy are similar to those observed in the kidney. Hypothesis: Diabetic patients at risk of developing nephropathy can be identified prior to the development of microalbuminuria by their pattern of microcirculatory responses to activation and blockade of the renin-angiotensin system. We propose to identify differences in the skin blood flow responses to pharmacological manipulations of the cuatneous renin-angiotensin system between healthy subjects, patients with diabetes without microalbuminuria, and patients with diabetes with micro or macroalbuminuria. Methods: Drug delivery will be achieved by intradermal microdialysis combined with local skin blood flow measurements by laser-Doppler flowmetry. Healthy volunteers and subjects with diabetes (males and females) will be included in this study. Patients with diabetes and with normal urine albumin excretion rates or with microalbuminuria will have normal blood pressure (<130/80) and normal renal function (serum creatinine < 1.2 for women, <1.3 for men). We have already characterized the skin RAS in normal volunteers. This will allow us to compare the responses to manipulations of the RAS between healthy subjects and patients with diabetes with and without nephropathy. We anticipate finding changes in the skin microcirculation mediated by the RAS that precede the appearance of microalbuminuria that may allow us to predict which diabetic patients are at risk to develop nephropathy. Long-term studies will include the correlation of these phenotypic findings with known mutations in the angiotensin II type 1 receptor and angiotensin converting enzyme genes.